Based on the lessons learned from our project on carbocyclic nucleosides (Z01 BC 006174) regarding the mechanism of "delayed chain termination", three lines of investigation have been implemented to exploit each of the critical parameters necessary for efficient activity against HIV resistant lines: 1) introduction of a 4'-alkyl group of tunable bulk in a 2'-deoxyribose moiety; 2) introduction of an extra OH group elsewhere in the molecule of a 2',3'-dideoxysugar moiety to allow limited chain elongation; and 3) the incorporation of a double bond in the ribose moiety to achieve ring flatness, a property deemed essential for efficient phosphorylation by cellular kinases. Progress in these three areas is highlighted. 1) A thymidine analogue bearing a 4'-methyl group showed excellent properties as a delayed chain terminator when used in vitro against HIV-RT as the 5'-triphosphate, but failed to be recognized by cellular kinases. The compound demonstrated excellent anti-HIV activity only in cells transfected with the herpes thymidine kinase gene. In view of the importance of the nucleobase for the selection of specific cellular phosphorylation pathways, the synthesis of similar 4'-methyl-2'-deoxypurine analogues is ongoing. 2) Synthesis of a 2',3'-dideoxy adenosine analogue with a 3'-CH2OH chain was completed and studied. In conformational terms the position of the terminal OH of the new chain was to allow recognition by cellular kinases and to provide the polymerase the opportunity of limited chain elongation. This compound failed to displayed in vitro anti-HIV activity suggesting probable failure as a kinase substrate. Studies with the 5'-triphoshate analogue are in progress to determine if it operates as a delayed chain terminator. 3) In view of the reported anti-HIV activity of the natural product oxetanocin A, a compound with a flat oxetan ring, synthesis of a riboside combining a 4'-CH2OH for chain elongation and a 2',3'-double bond to achieve ring flatness is in progress.